It is generally believed that abnormalities in either the processing of the amyloid protein precursor (APP) and/or the accumulation of the amyloid protein (A/beta) derived from APP play a central role in the etiology of Alzheimer's disease (AD). For this reason, understanding the function of APP and its catabolic fragments, as well as identifying the regulators of APP expression, APP processing, A/beta formation, and A/beta accumulation, are important steps towards understanding the causes of AD and defining therapeutic targets for this disease. This grant application is to support a multi-disciplinary study of APP function, expression, trafficking and processing. Dr. Nairn's project will include: identification and characterization of proteins that interact with the intracellular domain of APP; analysis of the effects of phosphorylation of APP on its interaction with these proteins; and, analysis of the effects of these APP binding proteins on APP processing. Dr. Gandy's project will include: study of the regulation of APP metabolism in in vitro cell-free protein processing and trafficking assays; study of the regulation of APP and alpha-factor processing in wild-type and modified Saccharomyces cerevesiae; and, study of the regulation of the level and turnover of various APP holoforms and metabolites within subcellular fractions and isolated organelles. Dr. Greengard's project will include: identification of isoforms of protein kinases and protein phosphatases involved in the regulation of APP processing; characterization of the role protein phosphatase plays in regulating APP expression and processing in vivo; and, identification and characterization of proteins that interact with the extracellular domain of APP. Core will include: the production and supply of key reagents, including knockout mice, enzymes and antibodies for the other sections of the Program Project.